ALBERT

Description: Introduction: Ibrutinib is a Bruton tyrosine kinase inhibitor approved for the treatment of first-line (1L) and relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). Original approval of ibrutinib was based, in part, on results from the RESONATE and RESONATE-2 studies demonstrating improved efficacy of ibrutinib among R/R CLL patients. Data from the trial reported as few as 4% of participants required dose reduction and 4% discontinued treatment because of adverse events (AEs). Real-world studies have demonstrated that the rates of dose reductions and discontinuations of ibrutinib because of AEs are significantly higher (as high as 25%). The aim of this study was to analyze baseline characteristics of patients with CLL who were treated with ibrutinib in the community setting, as well as the subsequent rates of and reasons for dose reductions and discontinuations. Methods: We conducted a retrospective chart review of 50 randomly selected patients of RCCA, a large medical oncology group in New Jersey with 13 practices over 30 sites that services approximately 1200 patients with CLL annually. Patients with a diagnosis of CLL were included if ibrutinib therapy was started between March 2014 and June 2019, and they had a minimum of 6 months of follow-up on therapy and were 18 years of age or older. Exclusion criteria were participation in a trial involving ibrutinib, active treatment for another malignancy, and pregnancy. The index date was defined as the date of novel agent initiation. De-identified data collected for descriptive analysis were used to summarize patient and disease characteristics, as well as to identify reasons for dose reduction and discontinuation. Result: 50 Patients with CLL were included in this analysis; 21 (42%) received ibrutinib as 1L therapy and 29 (58%) for R/R disease. Patient and disease characteristics at baseline are shown in Table 1. 17 Patients (34%) underwent at least 1 dose reduction. Most dose reductions were due to AEs, and 1 reduction was due to a drug-drug interaction. The most common category of AE that led to dose reduction was gastrointestinal disorders (n=4 [24%]) (Table 2). In our study, 15 patients (30%) discontinued treatment. Of these discontinuations, 10 (66%) were due to AEs, 2 (13%) were due to deaths, and 2 (13%) were due to progression of disease. The most common AE for drug discontinuation was atrial fibrillation (n=3 [20%]) (Table 2). The median follow-up time for all patients was 21.5 months. For those who underwent dose reduction (n=17), median time to dose reduction was 1.9 months. Median time to discontinuation of treatment was 6.9 months overall (n=15), whereas median time to discontinuation specifically due to AEs (n=10) was 3.4 months. Conclusion: Patients with CLL who were treated with ibrutinib in the real-world setting frequently experienced dose reductions and treatment discontinuations. In our medical oncology practice, about one-third had their treatment dose reduced and about one-third had treatment discontinued. We found much higher rates than those originally reported in the RESONATE and -2 studies, with rates closer to those found in other real-world analyses. This is probably because patients with preexisting conditions and concurrent medication use may be excluded from clinical trials, resulting in a healthier participant population. For example, based on the RESONATE trial's exclusion of patients taking warfarin or strong CYP3A4/5 inhibitors, about one-fifth of our patients would have been excluded from that study. Further research is still needed to gather population characteristics and responses to therapy that may help guide clinicians in the optimal management of patients with multiple comorbid conditions and concurrent medications who are receiving ibrutinib for CLL. Disclosures Du: AstraZeneca: Other: Grant. Fang:AstraZeneca: Other: Grant. Yeung:AstraZeneca: Research Funding. Peng:AstraZeneca: Other: Grant. Keck:AstraZeneca: Other: Grant.

Description: Background: Novel coronavirus infection (SARS CoV-2 or COVID-19) is associated with a high risk of thrombotic complications, including macro- and micro-thrombi in major organs, leading to increased morbidity and mortality. Anticoagulant use, mainly heparin, which has both anticoagulant and anti-inflammatory properties, has been suggested as potentially beneficial. However, the optimal dose of anticoagulant for patients with COVID-19 is unknown. Establishing the optimal thromboprophylaxis strategy and determining the role of biomarkers for patient risk stratification may help to improve outcomes in COVID-19. Methods: This single-center retrospective cohort study is part of an ongoing Quality Improvement project on the use of an anti-factor Xa-driven heparin protocol, which includes a low-dose intravenous (IV) unfractionated heparin (UFH) option, being conducted at our medical center. Data on the type, dose, and indication for anticoagulation as well as outcomes including thrombosis, bleeding and survival was collected for inpatients diagnosed with COVID-19 between mid-March and June 15, 2020. To address COVID-coagulopathy we developed a d-dimer-based anticoagulation protocol for patients with COVID-19 (Figure 1). We recorded anticoagulant use as either standard prophylactic, escalated prophylactic (low-dose intravenous unfractionated heparin titrated to achieve an anti-factor Xa level of 0.1-0.3 anti-Xa units or enoxaparin 0.5mg/kg subcutaneously every 12 hours) or standard therapeutic dose used during the hospitalization. The primary endpoints assessed were ISTH-defined major and clinically relevant non-major bleeding (CRNMB) events and survival. Secondary endpoints included incidence of breakthrough thrombosis and duration of hospitalization. Results: A total of 263 patients with COVID-19 were reviewed. Of these, 68.44% of patients received prophylactic, 12.55% escalated prophylactic and 19.01% therapeutic dosage. Of total, 129 (49%) were receiving ICU level of care. No major bleeding events were observed. The incidence of CRNMB was 4.56% in the whole cohort, which did not differ significantly between the escalated prophylactic and therapeutic groups (12% and 12.12%, respectively). Patients treated with standard prophylaxis had less CRNMB (1.11%), but this was not statistically significant in a multivariate analysis that included other confounding factors such as age, sex, ethnicity, BMI, comorbidity, HASBLED bleeding risk, and sepsis induced coagulopathy score (SICS). The mortality rate was 12.6% in the whole cohort (7.22%, 21.21% and 26% in prophylactic, escalated prophylactic, and therapeutic dosage, respectively). Factors significantly associated with increased mortality included age and ICU level of care (HR 1.10, 95%CI [1.05, 1.15] and HR 20.42, 95%CI [2.84, 146.72], respectively). The use of therapeutic dose heparin and high-flow nasal cannula demonstrate a survival benefit in multivariate analysis (HR 0.13, 95%CI [0.04,0.44] and HR 0.23, 95%CI [0.07, 0.72], respectively; Figure 2). Breakthrough thrombosis occurred in 7 (2.66%) patients; 1 (0.56%), 1 (3.03%) and 5 (10%)) in prophylactic, escalated prophylactic and therapeutic dosage, respectively but very few diagnostic tests were performed during this time period. Duration of hospitalization was significantly longer in the therapeutic dose group when compared to escalated prophylaxis and standard prophylactic groups. Conclusion: In this cohort of inpatients with COVID-19, there were no major bleeding events related to any dose of heparin or LMWH prophylaxis. By multivariate analysis, implementation of a d-dimer-titrated anticoagulation strategy was not associated with increased CRNMB. Therapeutic dose heparin based on a d-dimer-driven anticoagulation protocol was associated with a survival benefit in COVID19-infected patients. Limitations of this study include the retrospective observational nature and a lack of a uniform diagnostic protocol for patients with suspected VTE. Although no significant difference in bleeding events were observed in our study subgroups, randomized clinical trials are necessary to determine optimal thromboprophylaxis strategy in the COVID-19 population. Disclosures No relevant conflicts of interest to declare.

Description: Introduction: Since its approval in 2014, ibrutinib has replaced chemotherapy to become a preferred therapy for CLL patients. Real-world studies of ibrutinib in CLL patients have shown higher rates of discontinuations due to adverse events (AEs; 14-23%) compared with data from the early clinical trials of ibrutinib (4-9%). Similarly, dose reduction rates due to AEs in the real-world studies were 22-28%, vs 9% in the ibrutinib package insert. These real-world studies have been mostly focused on the academic setting or based on registry data. This study was part of an initiative to collect chart-review data from an academic practice and broader community networks, using an identical protocol to describe ibrutinib dose reductions and discontinuations in CLL patients. Methods: This was a multicenter, retrospective, chart review study of CLL patients and treated with ibrutinib. De-identified data were pooled from 2 community networks and 1 academic practice. Each community network agreed to contribute 50 patients on ibrutinib to the pooled data. To minimize potential bias, the patients were randomly selected from all the ibrutinib-treated patients in each network. All patients meeting inclusion criteria from the academic site were included. Inclusion criteria were: confirmed diagnosis of CLL, initiation of ibrutinib between March 2014 and June 2019, and ≥18 years of age at the initiation of therapy. Patients were excluded if they were actively receiving therapy for other primary cancers or were enrolled in a clinical trial of ibrutinib during the study period. Index date was defined as the date of ibrutinib initiation, and patients were followed for a minimum of 6 months. Variables collected included: patient demographics, clinical and treatment characteristics, molecular profiles, and reasons for dose reduction and discontinuation. Descriptive statistics were used to summarize the results. Results: 180 CLL Patients were included in this analysis. Of these, 56 (31%) patients received ibrutinib in the first line (1L) and 124 (69%) patients received ibrutinib in a relapsed/refractory (R/R) line. Over half (56%) of patients were treated in a community setting. Baseline demographic and clinical characteristics are shown in Table 1. 1L Ibrutinib patients had a median follow-up of 26 months. Twenty-five percent of patients (n=14) experienced at least one dose reduction, mainly due to AEs (n=11, 79%) (Figure 1). There was no single AE primarily responsible for dose reduction (Table 2). Treatment discontinuations were reported in 20% of patients, and they were more commonly due to AEs (73%) than disease progression (9%). Similarly, a variety of AEs led to discontinuations (Table 2). Median time to the first dose reduction for 1L patients was 9.9 months. Among patients who discontinued ibrutinib, median duration of treatment (DOT) was 15 months; with median DOT of 6 months for those who discontinued because of AEs and 28.9 months for those who discontinued because of progression. R/R Ibrutinib patients had a median follow up of 28.5 months. About a quarter (27.5%, n=34) of patients experienced at least 1 dose reduction, mainly due to AEs (n=30 [88%]) (Figure 1). The most common AEs leading to the first dose reductions were gastrointestinal (GI) disorder (43%), fatigue (23%), , and arthralgia/myalgia/musculoskeletal pain (17%) (Table 2). Treatment discontinuation was reported in 40% of patients, with over half due to AEs (58%) rather than disease progression (18%). The most common AEs leading to discontinuation were GI disorders (31%), atrial fibrillation (24%), and infections (21%) (Table 2). Median time to the first dose reduction in R/R patients was 3.1 months. Among patients who discontinued ibrutinib, median DOT was 9 months; with median DOT of 6 months for those who discontinued because of AEs and 30.2 months for those who discontinued because of progression. Conclusions: Dose reductions and discontinuations were frequent in CLL patients receiving ibrutinib in routine clinical practice. Compared with ibrutinib clinical trial data at a similar follow-up time, AEs were the most common reasons leading to discontinuation of ibrutinib rather than disease progression. The rates of dose reduction and discontinuations due to AEs in our study were higher than in clinical trials and were consistent with other real-world studies, indicating similar patterns in both community and academic settings. Disclosures Hou: Verastem: Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Other: PI; AbbVie: Consultancy, Other: PI; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding. Ryan:AstraZeneca: Current Employment, Current equity holder in private company. Du:AstraZeneca: Other: Grant. Fang:AstraZeneca: Other: Grant. Marks:Sanofi: Research Funding. Page:AstraZeneca: Other: Grants. Peng:AstraZeneca: Other: Grant. Szymanski:AstraZeneca: Current Employment, Other: Stockholder. Le:AstraZeneca: Current Employment, Current equity holder in private company.